Actas Dermosifiliogr.

2011;102(10):766---779

CONTROVERSIES IN DERMATOLOGY

Propranolol in the treatment of infantile hemangioma: clinical

effectiveness, risks, and recommendations夽
I. Sánchez-Carpintero,a,∗ R. Ruiz-Rodriguez,a J.C. López-Gutiérrezb

a
Servicio de Dermatología, Clínica Ruber, Madrid, Spain
b
Servicio de Cirugía Pediátrica, Hospital Infantil La Paz, Madrid, Spain

Received 22 January 2011; accepted 11 May 2011

KEYWORDS Abstract The therapeutic arsenal for hemangiomas in early childhood can now be considered
Hemangioma; to include oral ␤-blockers, mainly propranolol. These drugs are thought to act as vasocon-
Angioma; strictors, regulating angiogenic pathways and inducing apoptosis of vascular endothelial cells.
Vascular tumor; Although infantile hemangioma is not among the approved indications for ␤-blockers, many
Propranolol; specialized clinics will prescribe propranolol before resorting to corticosteroids. A dosage of
␤-blockers; 2 mg/kg/d, is usually employed with a dosing interval of 8 hours. Propranolol is safe, causing
Adverse events few side effects, although cases of hypoglycemia, hypotension, diarrhea, reflux, cold hands and
feet, bronchospasm, and hyperkalemia have been described. Generally, these adverse effects
have not had serious consequences. Prescription in PHACE syndrome is controversial. In all
cases, a cardiologist should assess the patient before treatment begins, blood pressure should
be monitored, and pediatric follow-up should be scheduled. This review covers our current
understanding of the indications, clinical response, and adverse effects of propranolol, a drug
has revolutionized our attitude toward infantile hemangioma and the way we approach therapy.
Clinical trials under way are also reviewed.
© 2011 Elsevier España, S.L. and AEDV. All rights reserved.

PALABRAS CLAVE Propranolol en hemangiomas infantiles: eficacia clínica, riesgos y recomendaciones

Hemangioma;
Resumen Los ß-bloqueantes orales ---principalmente el propranolol--- se consideran una opción
Angioma;
más en el tratamiento de los hemangiomas infantiles. Se ha sugerido que pueden actuar a
Tumor vascular;
través del efecto vasoconstrictor, mediante la regulación de las vías implicadas en la angiogé-
Propranolol;
nesis y ocasionando apoptosis de las células endoteliales. Aunque su uso no está aprobado
␤-bloqueante;
para esta indicación, en muchos centros se indican antes que los corticoides. La dosis más
Efectos secundarios
empleada es 2 mg/kg/día repartida cada 8 h. Es un fármaco seguro con escasos efectos secun-
darios. Se ha descrito hipoglucemia, hipotensión, diarrea, reflujo, frialdad de manos y pies,

夽 Please cite this article as: Sánchez-Carpintero I, et al. Propranolol en hemangiomas infantiles: eficacia clínica, riesgos

y recomendaciones. Actas Dermosifiliogr. 2011;102:766-779.

∗ Corresponding author.

E-mail address: ignacio@ricardoruiz.es (I. Sánchez-Carpintero).

1578-2190/$ – see front matter © 2011 Elsevier España, S.L. and AEDV. All rights reserved.
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations 767

broncoespasmo e hiperpotasemia, generalmente sin repercusiones graves. Su indicación en el

síndrome de PHACES es controvertida. Antes de iniciar el tratamiento se recomienda en todos
los casos la realización de una evaluación cardiológica, la determinación de la presión arterial
y el seguimiento pediátrico. En esta revisión se evalúan los conocimientos actuales sobre las
indicaciones, la respuesta clínica, los efectos secundarios y los ensayos clínicos en curso de
esta modalidad terapéutica que ha revolucionado la visión y el abordaje de los hemangiomas
infantiles.
© 2011 Elsevier España, S.L. y AEDV. Todos los derechos reservados.

Introduction use of ␤-blockers to treat hemangiomas of infancy. Propra-

Hemangiomas of infancy are benign vascular tumors that
develop in 3 phases: in the first, the tumor proliferates, the
second is a rest phase, and the third is marked by tumor
involution. The unanimous opinion is that these heman-
giomas should be treated in the proliferative phase under
the following circumstances: vision is affected or might be,
visceral organ involvement may become life-threatening,
rapid growth leads to anatomical distortion that may resolve
only partially and leave sequelae, an airway is affected, and
the tumor is causing congestive heart failure.1,2 Although a
wait-and-see approach to uncomplicated infantile heman-
giomas persists, an interest in more active management has
begun to emerge. A passive attitude might be justified by
the benign nature of these tumors and their tendency to
resolve spontaneously, but many patients still require inter-
vention at the end of the period of involution if the tumor
has not completely disappeared. The difficulty of predicting
how long involution will take and how complete it will be jus-
tifies taking a more active approach to starting treatment at
an early age.3
Treatment should be decided on the basis of individ-
ual circumstances, such as the size and location of the
tumor, complications, the phase at the time of evaluation,
the involvement of other organs, and psychological fac-
tors. Here we will discuss the novel and highly promising
nolol is proving very effective in this setting and its use is
therefore growing. As a result, surgical intervention is usu-
ally needed only when involution has been incomplete and
removal of residual tissue or other corrective measures are
required.
Corticosteroids or ␤-Blockers?
Oral corticosteroids have been the drugs of choice for treat-
ing complicated hemangiomas of infancy to date,4 but oral
␤-blockers, which lead to better overall outcomes with
few adverse effects, will probably overtake them in the
near future. Although some practice guidelines still empha-
size corticosteroids for first-line therapy, few of the major
referral centers currently prescribe corticosteroids before
propranolol. Our protocol has specified ␤-blockers as first
choice for the last 2 years.
Accumulated clinical experience suggests that segmen-
tal hemangiomas (Fig. 1) respond better to propranolol
than to oral corticosteroids; this is the reason we rec-
ommend propranolol as the first-line treatment. In focal
hemangiomas (Fig. 2) outcome differences may be less pro-
nounced; corticosteroid treatment can therefore still be
considered, especially if the drug is to be injected directly
into the tumor. Topical corticosteroids, such as 0.05% clobe-
tasol propionate, have proven effective in small, superficial

Figure 1 A, Segmental hemangioma in a 3-month old. B, Marked response after 3 months of treatment with propranolol
(2 mg/kg/d). C, At 9 months, when treatment ended, the hemangioma had practically disappeared and there were no sequelae.
768
Figure 2 A, Four-month-old boy with a focal hemangioma on the auricle. B, After treatment with 2 mg/kg/d of oral propranolol,
resolution was nearly complete after 4 months.
hemangiomas of infancy.5 It therefore seems more reason-
able to prescribe topical clobetasol in such cases rather than
propranolol, although topical ␤-blockers such as timolol can
also be considered.
The treatment of hemangiomas of infancy has changed
dramatically as a result of numerous reports of tumors
that respond to propranolol after failing to respond
to corticosteroids.6 With increased first-line use of ␤-
blockers, it will soon be impossible to know whether
the hemangiomas so-treated might also have responded
to corticosteroids. Two valuable clinical trials are cur-
rently comparing these treatments, however7 : one trial calls
for prescribing corticosteroids versus propranolol and the
other a combination of a corticosteroid plus either pro-
pranolol or placebo (Table 1). Oral corticosteroid-treated
patients who later also take propranolol, while being
weaned from the corticosteroids, respond satisfactorily,
similarly to those who receive propranolol alone. Com-
bined treatment, therefore, does not seem to make much
sense.
Another interesting new aspect of propranolol therapy is
the response of hemangiomas during the involutional phase
in children aged 2 or 3 years.8---10 Propranolol is effective
in this phase whereas corticosteroids only act during the
proliferative phase. Response is less marked with delayed
treatment and is absent in some cases, but experience
suggests that trying treatment for at least 3 months is
reasonable in many cases in which tumor involution is incom-
plete or slow.
␤-Blockers
␤-Blockers antagonize the ␤-adrenergic pathway, blocking
receptors in such organs as the heart, the pancreas, and the
liver, as well as in peripheral blood vessels and bronchi. Some
of these drugs (oxprenolol, pindolol, acebutolol, celiprolol)
have intrinsic sympathomimetic activity, defined by an abil-
ity to both stimulate and block adrenergic receptors; thus,
there is less risk of effects such as bradycardia and cold in
the lower extremities. ␤-Blockers can also be grouped as
I. Sánchez-Carpintero et al.
cardioselective or not, or as lipophilic versus hydrophilic.
Hydrosoluble agents (eg, atenolol, celiprolol, nadolol, and
sotalol) penetrate brain tissue to a lesser degree and cause
fewer sleep disorders. Propranolol is a noncardioselective
␤-blocker.
Relatively short-acting ␤-blockers are taken 2 or 3 times
daily, while others----such as atenolol, bisoprolol, carvedilol,
and nadolol----can be taken in a single daily dose. Oral
propranolol is fully absorbed, reaching maximum plasma
concentration 1 or 2 hours after intake on an empty stom-
ach. Up to 90% of the drug is metabolized in the liver and
the mean half-life is 3 to 6 hours. The recommended dosing
schedule is every 8 hours. Propranolol is distributed rapidly
throughout the tissues, reaching high concentrations in the
lungs, liver, kidneys, brain, and heart. Protein binding is 80%
to 95%.
The principal indications for propranolol are hyperten-
sion, angina, acute myocardial infarct, certain arrhythmias,
heart failure and hyperthyroidism, but it is also used
to alleviate anxiety, to treat glaucoma, and to prevent
migraine. Given that infantile hemangioma is not yet listed
as an approved use of propranolol in the summary of
product characteristics, its prescription must be carefully
explained to families and their written informed consent
obtained.
␤-Blockers and Hemangiomas of Infancy
␤-blockers (mainly propranolol) joined the therapeutic arse-
nal as soon as their effectiveness in hemangiomas of
infancy was first reported in 2008.11 In most treatment cen-
ters they are considered the first line of therapy for this
skin tumor even in the absence of official approval. The
first report of use was in a series of 11 patients whose
hemangiomas responded remarkably well to the drug,11
and that success was subsequently confirmed by publica-
tions of new case series and reports of single cases. Only
hemangiomas of infancy seem to respond to propranolol
(Fig. 3). Lack of response has been observed in congenital
hemangiomas and tufted angiomas (J.C.L.-G., unpublished
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations
Table 1 Current Clinical Trials to Test ␤-Blocker Treatment for Hemangiomas of Infancy.
Original Title
Double Blind, Randomised, Placebo-Controlled Study of
Propranolol in Infantile Capillary Hemangiomas
Propranolol Versus Prednisolone for Treatment of Symptomatic
Hemangiomas
Propranolol vs Prednisolone for Infant Hemangiomas----A
Clinical and Molecular Study
Nadolol for Proliferating Infantile Hemangiomas: A Prospective
Open Label Study With a Historical Control
Open-label, Uncontrolled Study of the Off Label Use of
Propranolol for Infancy Hemangiomas to Identify Side Effects
Topical Timolol 0.5% Solution for Proliferating Infantile
Hemangiomas: A Prospective Double Blinded Placebo
Controlled Study
A Comparative Study of the Use of Beta Blocker and Oral
Corticosteroid in the Treatment of Proliferative and
Involuting Cutaneous Infantile Hemangioma
Corticosteroids With Placebo Versus Corticosteroids With
Propranolol Treatment of Infantile Hemangiomas
A Randomised, Controlled, Multidose, Multicentre, Adaptive
Phase II/III Study in Infants With Proliferating Infantile
Hemangiomas (IHs) Requiring Systemic Therapy to Compare
4 Regimens of Propranolol (1 or 3 mg/kg/day for 3 or 6
Months) to Placebo (Double Blind)
Source: http://clinicaltrials.gov/ 7
observations), as well as in other vascular lesions, such
as pyogenic granuloma, which are negative on GLUT-1
staining.10
Mechanism of Action
The ultimate mechanism of action of ␤-blockers in this
setting has not been determined, but 3 possibilities
have been suggested12 : a) there may be a vasoconstric-
tive effect, reflected in the change in coloring; b) the
expression of proangiogenic genes may be downregulated
via reduced activity of the Raf-mitogen-activated protein
kinase pathway (reducing the expression of factors such
as vascular endothelial growth factor and basic fibroblast
growth factor)13 ; and c) endothelial cell apoptosis may be
induced.14
Current research seems to suggest that heman-
giomas of infancy and retinopathy of prematurity share
769
Objectives and Study Design
- To determine the efficacy of 1 mo of treatment with
propranolol (3mg/kg/d for 15 d, then 4 mg/kg/d for 15 days)
vs placebo in infants <4 mo old for whom treatment is not
imperative
- Oral propranolol 0.5 mg/kg, 4 times/d, for 4-6 mo
- Oral prednisolone, 1 mg/kg twice daily, 4-6 mo
- Oral nadolol, 0.5 mg/kg/d, taken in 2 fractions Weekly dose
increases (0.5 mg/kg/d) if blood pressure and heart rate are
acceptable, up to 2 mg/kg/d
- Initial treatment with 1 mg/kg/d of propranolol, increased
after 24 h or longer if 3 sequential doses have been well
tolerated without bradycardia or other adverse events
- Propranolol treatment of complicated hemangiomas vs
physical treatment (cryotherapy or laser therapy) in a
comparison group of 16 patients
- Propranolol 2 mg/kg/d in 3 fractions with or without
concomitant therapy (surgery, laser therapy)
- Topical 0.5% timolol in aqueous solution (2-3 drops) twice
daily
- Oral propranolol, 2 mg/kg/d in 2 fractions for 60 d
- Oral prednisone, 2 mg/kg/d, in 2 fractions for 60 d
- Oral prednisolone, 1-2 mg/kg/d for 7 days followed by slow
dosage reduction until withdrawal of treatment after 3 wk (2
mo of treatment in total), with placebo
- Oral prednisolone, 1-2 mg/kg/d for 7 d followed by slow
dosage reduction until withdrawal of treatment after 3 wk (2
mo of treatment in total), with oral propranolol, 2 mg/kg/d
- Oral propranolol, 1 or 3 mg/kg/d for 3 or 6 mo
mechanisms involving a key role for vascular endothe-
lial growth factor.15 The proposed use of ␤-blockers for
retinopathy of prematurity16 is based on observations in an
oxygen-induced animal model of the condition, in which top-
ical timolol has been shown to prevent retinopathy in 40%
of the cases and to mitigate its severity in remaining cases.
Our need for a better understanding of the pathogenesis
of this disease and its response to ␤-blockers has opened a
new line of investigation that will also help us understand
the mechanism that underlies their effect in hemangiomas
of infancy.
Adverse Events
␤-blockers slow heart rate and depress myocardial activ-
ity and are therefore contraindicated in patients diagnosed
with second- or third-degree heart block. They should also
be avoided in progressive or unstable heart failure, severe
770
Figure 3 A, A 6-month-old girl with a parotid hemangioma. B-D, The response to propranolol (2 mg/kg/d) was rapid after 2, 3,
and 5 months, respectively.
bradycardia, hypotension, sinus node diseases, and car-
diogenic shock. These drugs can trigger an asthma crisis
and prescription to asthmatics or in situations of bron-
chospasm should be avoided. Other effects that might
appear are severe hypotension, bradycardia and conges-
tive heart disease, digestive system disorders, shortness
of breath, fatigue, sleep disorders (such as nightmares or
insomnia), paresthesia, nausea and dizziness, depression
and other psychological disorders, purpura, thrombocytope-
nia, hallucinations, exacerbation of psoriasis and alopecia,
fatigue, and cold extremities. These drugs can also impair
glucose tolerance and interfere with the metabolic and veg-
etative response to hypoglycemia. Other adverse effects
that are the consequence of peripheral vasoconstriction are
intermittent claudication and Raynaud syndrome. The fre-
quency of many of these effects can be diminished by using
selective ␤1 -blockers.
Generally speaking, oral propranolol is safe in chil-
dren and associated with few adverse events17 ; therapy
needs to be withdrawn only rarely. Although unforeseen
long-term side effects might still develop, we must remem-
ber that propranolol is a drug that has been used for
some 50 years and has proven safe in children as well
I. Sánchez-Carpintero et al.
as in adults.18,19 We note, therefore, that the possible
side effects of propranolol are currently being contrasted
with those of oral corticosteroids. What tests do we
order before prescribing oral corticosteroids for these
patients? We do not check hypothalamic-adrenal function-
ing, nor do we monitor the immune system or check
blood pressure systematically. Why should infants who
are candidates for propranolol therapy be admitted to
hospital and an echocardiogram ordered, blood pressure
checked, and blood sugar determined? Propranolol tox-
icity is unquestionably mild: by mistake, a patient in
our hospital ingested a dose that was 10-fold higher
than prescribed for 3 days and developed only moderate
hypotension. In contrast, oral corticosteroid therapy has
been linked to a patient’s death,20 and in our hospital
we witnessed a death due to cryptococcal infection sec-
ondary to the immunodepressive effects of 9 months of
corticosteroid therapy to treat a segmental hemangioma
(J.C.L.-G., unpublished observations). Should such a death
occur in relation to propranolol treatment, it would prob-
ably be the subject of a lead article in a high-impact
journal. However, we do take heed of a recent com-
mentary recalling the initial enthusiasm for interferon, a
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations 771

drug that is hardly prescribed now because of irreversible complications,29 even in premature infants being treated for
neurologic effects; propranolol use might still have a similar other conditions.30,31 Also supporting safety is the lack of any
history.21 reports of serious complications when ␤-blockers have been
Few serious adverse events in infants treated with used to treat hemangiomas of infancy.
propanolol for hemangioma have been reported. Three
patients developed severe hypoglycemia (associated with What Dose Regimen Is Right and How Long Should
hypothermia in 2 infants).22 Cases of bradycardia and
Treatment Last?
hypoglycemia21 or hypoglycemia alone23 have also been
reported. In another case, an infant with multiple hepatic
Dose regimens have varied from series to series. Most have
and cutaneous hemangiomas, without brain involvement,
called for 1 to 3 mg/kg/d of propranolol divided into 3
had a seizure caused by hypoglycemia.24 Hypoglycemia is
doses.6,32 We found a single report of using dose increments
known to be more common in the neonatal period and
until 2 mg/kg/d was reached in 2 patients, who took the
therefore its development must be watched for, but it
drug twice a day and experienced no adverse effects such as
does not seem to be dependent on propranolol dose as
hypoglycemia.33 Propranolol is usually taken orally; because
it has been reported in patients on low-dose regimens of
a formulation appropriate for use in hemangioma of infancy
1 to 2 mg/kg/d.22 Likewise, hypoglycemia does not seem
is not yet available commercially, a solution in syrup is pre-
to be a complication that develops on initiating treatment,
pared. One report described injecting the drug intravenously
as it has been detected in patients after as long as 9
for the first 5 days of treatment in 1 infant.34 Thus, no dosing
months on propranolol. Although long periods of fasting
regimen, including duration and monitoring periods, has yet
have been blamed for hypoglycemia, a clear association
been defined. We have observed no differences in clinical
has not been established: low blood sugar has been known
response with dosages of either 2 or 3 mg/kg/d, and have
to appear only 2 to 3 hours after a meal. Therefore, par-
elected to begin with the 2-mg daily amount in a 3-dose
ents have been warned to avoid long periods of fasting,
regimen and maintain it if the clinical response is good.
although frequent feeding does not seem to offer an infal-
Experience thus far does not suggest that the rate of adverse
lible safeguard against this complication. It also does not
effects rises when the initial dosage is 2 mg/kg/d in compar-
seem to help to avoid dose increases at the start of ther-
ison with a regimen of gradual increases building up to that
apy or to take propranolol in 2 or 3 fractions of the daily
level.
dose. Given the uncertainties surrounding propranolol use,
Regrowth sometimes occurs if treatment is withdrawn
we must wonder if it is really necessary to closely monitor
when the tumor is still in the proliferative phase.35 Pro-
these infants, even hospitalizing them for 48 hours as some
pranolol can be restarted in these cases and the outcome
protocols have recommended. It seems more reasonable
is usually good,36 but the general recommendation is to
to educate parents to recognize the early signs of hypo-
maintain treatment until the proliferative phase has ended
glycemia (eg, sweating, trembling, tachycardia, hunger) and
or until 12 months of age.32 Hemangiomas of infancy do
late manifestations (eg, excessive sleeping, lethargy, apneic
not seem to disappear completely under propranolol treat-
episodes, seizures, poor appetite, loss of consciousness, and
ment; however, the areas of telangiectasis that often remain
hypothermia).
can be eliminated later by pulsed dye laser treatment
Diarrhea and reflux have also been described among the
(Fig. 4). Experience with other ␤-blockers, such as ace-
side effects of ␤-blockers. Diarrhea has only been reported
butolol or nadolol, is more limited.37 In our dermatology
in 3 infants treated for hemangiomas at twice-daily doses
department therapy is maintained until the age of 8 to
of 1 mg/kg25 and in 3 other infants in a series of 17 with
10 months or longer if the tumor continues to respond to
periocular hemangiomas.9 Diarrhea may also be caused by
treatment.
the excipient used in certain preparations of the drug in
The sudden withdrawal of propanolol in angina pectoris
maltitol-containing suspensions (the case of Syprol in the
can trigger or aggravate the angina and cardiac arrhyth-
United Kingdom).25 Allergic reactions are rare and may also
mia and even lead to acute myocardial infarction. In
be related to a compound in the excipient. Reflux has
hemangioma of infancy, gradual weaning does not seem
been described in around 10% of cases in a series of 30
to be necessary, although some hospitals do include a
patients.26 Parents also report cold hands and feet. More
period of dose reductions,6,34 theoretically minimizing the
worrying would be the possibility of hyperkalemia, which
risk of a hyperadrenergic response. Some authors propose
was recently described in 4-month-old girl under treatment
halving the dose for 2 weeks and then halving it again
for a hemangioma of the abdominal wall.27 High potassium
for 2 more weeks before stopping treatment entirely.6
concentrations were attributed in that case to massive lysis
Although propranolol is routinely withdrawn without a wean-
of hemangioma cells and impaired cell uptake of potassium
ing period and without adverse effects, it seems prudent
due to the effect of the ␤-blocker.
to advise gradual reduction so as to watch for regrowth
Caries developed in incisors after administration of pro-
and avoid any unforeseen problems. As tumor rebound
pranolol to a 10-month-old with a hemangioma on the lip.28
occurs gradually, it is easy to decide to restart treatment in
This complication might also be due to the excipient, which
time.
contained sucrose, or it may derive from reduced salivation,
a consequence of adrenergic antagonism. Finally, excessive
sleepiness was reported in around 27% of patients in a series Monitoring
of 30.26
Numerous publications report that propranolol is safe in No consensus has developed on how to monitor infants on
these young patients, with no reports of death or serious propranolol. Nor do we know that monitoring is strictly
772 I. Sánchez-Carpintero et al.

Figure 4 A, A 7-month-old boy with a scalp hemangioma. B and C, After propranolol treatment for 2 and 4 months (2 mg/kg/d)
improvement was substantial and included flattening of the lesion. D, The hemangioma did not fully disappear. Telangiectasis often
persists and can later be removed by pulsed dye laser.

necessary. Pretreatment evaluation by a pediatric cardiol-
ogist, unanimously believed to be essential, should include
an electrocardiogram and assessment of blood pressure
and heart rate. Some protocols also call for an echocar-
diogram, but we do not believe one is necessary if the
results of the previous tests are normal. Some hospitals
admit infants for the first 24 to 48 hours of treatment for
closer monitoring of blood sugar, blood pressure, and heart
rate,17 but a benefit of hospitalization has not been demon-
strated and this precaution seems to us and to others38
to be unnecessary. We recommend outpatient monitoring
of blood sugar, blood pressure, and heart rate 48 hours
after start of treatment. We then check blood pressure
and heart rate weekly in the first month and monthly
thereafter. Periodic blood sugar tests are not necessary.
As mentioned above, we believe it is more sensible to
teach parents how to recognize the symptoms of hypo-
glycemia.
Propranolol or Another ␤-Blocker?
Propranolol, a noncardioselective drug, has so far been the
most commonly prescribed ␤-blocker in infantile heman-
gioma. The few groups that have used other ␤-blockers
(nadolol and acebutolol) have reported similar results.37,39
As no trials have compared different ␤-blockers, there is no
reason to prefer one over another.
Blanchet and colleagues37 reported good clinical
response to acebutolol in 2 out of the 3 patients they
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations
treated for subglottic hemangiomas. Acebutolol is a selec-
tive ␤1 -blocker that theoretically has fewer side effects
than propranolol and is also easier to take, as dosing is
every 12 hours. The recommended regimen begins with
2 mg/kg/d and continues with gradual increases until
8 to 10 mg/kg/d.37 Sold in France under the trade name
of Sectral in a 40-mg/mL solution, this drug has been
used to treat arrhythmia and hypertension in pediatric
patients. Nadolol (sold as Solgol and used at doses similar
to those of propranolol) has also been effective in our
experience with over 20 patients (J.C.L.-G., unpublished
observations). Given the history of our clinical experience
with propranolol, it seems wise to continue using this
␤-blocker until information from additional trials becomes
available.
Topical ␤-Blockers
The success of oral propranolol suggested that topical
application might be effective in cases of small, superfi-
cial hemangiomas of infancy. In the first published series
of 6 patients with such hemangiomas, good response to
topical treatment was observed40 and has also been con-
firmed in isolated cases, such as that of a 4-month-old girl
with a periorbital hemangioma causing blepharoptosis and
covering the pupil.41 Substantial improvement (reduction
of size, thickness, and coloring) was seen when 0.5% tim-
olol maleate was applied twice a day for 5 weeks. In
another series, 5 patients were treated with timolol gel.42
Response was remarkable in 1 infant and was partial in the
remaining 4 infants, with no local or systemic side effects.
Response was also good in another recent case of heman-
gioma with PHACE syndrome, in which a timolol lotion was
applied.43
A randomized, double-blind placebo-controlled trial of
0.5% timolol in solution is now underway and will undoubt-
edly tell us more.7 In our experience with a small number
of cases, results have been uneven to date: while some
patients have improved significantly (Fig. 5) change has
scarcely been evident in others. Formulations of 0.1%
timolol gel and 0.5% timolol eye drops are available
for ophthalmologic use in Spain. Topical ␤-blockers can
be considered for treating uncomplicated small super-
ficial hemangiomas of infancy; this option should be
Figure 5 A, Superficial hemangioma on the lower eyelid of a 4.5-month-old baby girl. Twice-daily application of 0.5% timolol was
prescribed. B, Response began to be evident at 2 weeks, and C, was remarkable at 6 months, when the hemangioma had almost
fully disappeared.
773
weighed alongside alternatives such as imiquimod and
corticosteroids.5,44
Special Circumstances
Ulcerated Hemangiomas
Ulceration is the most common complication of infantile
hemangioma, affecting between 5% and 16% of patients.1,45
As resolution may not occur spontaneously for several
months, a physician should take an active approach to treat-
ing the ulcers. Oral corticosteroids and pulsed dye laser
treatment have both been found to be effective.46,47 Topical
imiquimod48 and becaplermin49 have also given satisfactory
results when applied.
Likewise, oral propranolol has been used successfully
in this setting,6,36,50,51 although not all ulcerated heman-
giomas respond and some may even worsen6,52 under this
treatment (Fig. 6). In a series of 30 infants with ulcer-
ated hemangiomas, 10 with small lesions responded well,
but the results for deeper ulcers were less satisfactory.6 In
another recent study of 33 infants with this complication,
a mean of 4.3 weeks was required to cure the ulcers of
30 patients.53
Periorbital Hemangiomas
Among the most important hemangiomas to treat early are
those located near the eye. Even 2 weeks of impaired
vision can lead to irreversible damage. The treatment of
choice until recently was oral or intratumoral corticos-
teroids. However, the possibility of embolization54 after
injection, causing occlusion of the retinal artery followed
by blindness, has led to reaction against intratumoral
injection.
Propranolol is thus a good alternative for treating
periorbital hemangiomas of infancy (Fig. 7). Most arti-
cles report rapid response, with remarkable reduction in
size within 48 to 72 hours of starting treatment.55,56 In
a series of 17 patients with periorbital hemangiomas,
the tumor shrank after only a month of treatment in
82%.9 The authors did not say so, but it can be inferred
that response differed according to whether the heman-
gioma was focal, segmental, or undetermined. In another
774 I. Sánchez-Carpintero et al.

Figure 6 A, The hemangioma of this 2-month-old baby girl affected the parotid, cheek, and lip, with associated ulceration. B
and C, Clinical response was highly satisfactory after 1 and 3 months of treatment with oral propranolol (2 mg/kg/d). D, At the end
of 9 months of treatment, there is redundant, atrophied tissue and slight deformity of the facial structure that can be treated with
laser surgery.

series, response was observed in all 10 infants treated
with 2 mg/kg/d of propranolol. Furthermore, the ambly-
opia of 5 of the infants improved substantially in 3 of
them.56 Outcome was good in all 4 patients in another
small series in which no side effects occurred during treat-
ment that started with low doses of 0.1 to 0.25 mg/kg/d
and increased to 2 mg/kg/d.8 Propranolol was even effec-
tive in a patient who started treatment at the age of 2 years,
5 months.
Airway Hemangiomas
Facial and cervical hemangiomas, which may compromise
the upper airway, are usually superficial, unilateral, and
subglottic.57 To date, corticosteroids have been the first-
line treatment, although a tracheotomy becomes necessary
in a large percentage (40%) of cases. Carbon dioxide laser
therapy can also be used.58
Various authors have reported propranolol to be effec-
tive in the treatment of upper airway hemangiomas,
most of which have been subglottic, and for most it has
been the first treatment chosen.59---61 Clinical improvement
was observed in all 14 patients in a series described by
Leboulanger and colleagues39 : airway obstruction was evi-
dent in only 22% after 2 weeks of treatment and in 12% after
4 weeks.
Resistance to propranolol has been observed in isolated
cases. Leboulanger and colleagues39 reported relapse when
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations 775

Figure 7 A, Infant girl at 6 weeks with a rapidly growing segmental hemangioma on the forehead and eyelid. Ptosis was marked
and progressive. On magnetic resonance the position of the entire eye could be seen to be shifted due to retrobulbar growth of the
hemangioma. Oral propranolol treatment was started at a dosage of 2 mg/kg/d. B, Improvement could already be seen at 72 hours.
C-F, Under this treatment the clinical course was highly satisfactory at 1.5, 3, 4, and 6 months, respectively.

propranolol was stopped after 1 month in a patient, and
when treatment was restarted resistance was noted. In
another patient whose airway was initially 95% occluded,
50% reduction was observed after 2 weeks of propranolol
treatment; however, obstruction increased again to 80%
after several months in spite of treatment with 2 mg/kg/d.62
These patients did not improve when the dosage was
increased.
In most reports, infants with airway hemangiomas have
also been receiving concomitant corticosteroids,10 but
776
remarkable improvement was recently reported in 2 infants
taking only propranolol from the start of treatment.33 Com-
bining the 2 therapies appears to be unnecessary.
Finally, we wish to highlight the case of a 12-month-old
who required ␤-mimetic drugs during cardiac surgery. He
had experienced good response to 6 months of treatment
with propranolol and was already on a low and decreasing
dose regimen (0.5 mg/kg/d) at the time of surgery. Tubes
could not be removed after surgery and a tracheotomy was
required. On examination, 95% of the airway was found to
be occluded. Increasing the propranolol dose to 2 mg/kg/d
reduced the stenosis again and after 1 month of treatment
only 5% of the airway remained obstructed.37
Good response to acebutolol, without adverse effects,
has also been described.37,39 Two out of 3 patients in 1
report responded satisfactorily to a regimen that started
with 2 mg/kg/d, taken in 2 doses, and was later increased
to 10 mg/kg/d.37
Hemangiomatosis and Visceral Hemangiomas
When multiple hemangiomas are distributed widely over
the surface of the body, the condition is termed heman-
giomatosis. When visceral organs are involved, the most
likely location for a hemangioma is the liver. When a
hepatic hemangioma is found in association with heman-
giomatosis, an infant is at high risk of heart failure63
and should be monitored regularly to detect complications
requiring prompt treatment. Fortunately, the prognosis
in these cases will surely change for the better, given
the satisfactory response to propranolol that has been
observed in some patients, in whom tumors have disap-
peared completely and the associated heart failure and
hypothyroidism have also resolved.64 There have also been
reports of cases of diffuse hepatic hemangioma that have
responded rapidly and definitively to propranolol, after prior
treatment with corticosteroids, vincristine, interferon, and
cyclophosphamide.65,66 Finally, life-saving treatment in iso-
lated cases of mediastinal, subglottic infantile hemangioma
have also been reported.67
Propranolol in Patients With PHACE Syndrome
For a diagnosis of PHACE syndrome it is not necessary
to observe all the characteristic findings: tortuosity of
large posterior (P) cerebral vessels, large facial heman-
giomas (H) accompanied by arterial (A), cardiac (C)
and eye (E) anomalies.68,69 In an estimated 70% of
PHACE syndrome cases, the infant has only extracu-
taneous manifestations. Dandy-Walker malformation has
been described among the cerebral abnormalities, along
with structural arterial abnormalities such as aneurys-
matic dilatations and abnormal branching of the internal
carotid artery.68 Cardiac defects and aortic malformations,
such as coarctation, may be present in a third of these
patients.70
The use of propranolol in infants with PHACE syndrome
is controversial as the drug may lead to potentially dan-
gerous complications such as cerebral infarct. Propranolol
is not contraindicated in patients with vascular steno-
sis, but ischemic strokes resulting from hypotension or
I. Sánchez-Carpintero et al.
bradycardia secondary to the ␤-adrenergic blockade are pos-
sible if this treatment is used when PHACE syndrome involves
arterial malformations with reduced flow.6,71 This compli-
cation has not been described to date, however, although
it must be admitted that the number of these patients
treated so far is very small.39,72 One very interesting study
that is relevant to this controversy looked at cerebral per-
fusion by single-photon emission computed tomography, a
technique that has proven useful in neurovascular condi-
tions such as Sturge-Weber syndrome.73 When 7 infants with
PHACE syndrome took 2 mg/kg/d of propranolol, the authors
observed normal uptake in frontal and temporal regions
after 3 or 6 months in spite of malformations that had been
identified by magnetic resonance angiography. Symptoms
and hemangioma size also improved significantly. Another
series included an infant with PHACE syndrome with aortic
coarctation and absence of the right vertebral artery; this
patient also responded well to propranolol.6 In conclusion,
when PHACE syndrome is suspected, a cardiologist should
perform a complete diagnostic work-up and neuroimaging
studies should be ordered to confirm the diagnosis before
starting propranolol treatment. Thus far, there is no rea-
son to assume that the incidence of stroke in infants with
PHACE syndrome is related to the treatment chosen; rather
it would be attributable to the degree of cerebrovascular
involvement. In fact, corticosteroids and interferon are used
indiscriminately in PHACE-syndrome patients in spite of the
antiangiogenic effects on the hemangioma and the brain, yet
these treatments are not reported to increase the incidence
of stroke.
Conclusions
␤-Blockers will probably become the treatment of choice
for hemangiomas of infancy in the near future, but many
points remain to be discussed. The optimal dose regimen,
the type of ␤-blocker that is most effective, and the type
of monitoring required during treatment, among other con-
cerns, must still be studied. Until we have more information
based on clinical experience and trials, we should be par-
ticularly cautious when prescribing. Given the excellent
responses to these drugs to date, however, the indica-
tions will certainly be increasing. Parents must be warned
that ␤-blockers are not yet approved for hemangiomas of
infancy----and it is helpful to mention that corticosteroids
are not so-approved either----and their written informed
consent must be obtained. Although adverse effects have
been described in isolated cases, we can say that ␤-
blockers are safe in infants with these tumors. Publications
describing ever larger series are confirming the absence
of adverse events,74 even in low-birth-weight newborns.75
Until the results of clinical trials become available, the pro-
tocols for monitoring infants during treatment will continue
to vary from hospital to hospital. In our opinion, outpa-
tient follow-up by a pediatrician seems to be the wisest
approach. We also recommend referring parents to special-
ists in vascular abnormalities for diagnostic confirmation and
prescription of this treatment. Diligent follow-up and com-
prehensive treatment should be provided, given that some
of these children may require additional laser or surgical
treatment.
Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations
Conflicts of Interest
Dr Juan Carlos López Gutiérrez is principal investigator
of the multicenter adaptive phase 2/3 randomized con-
trolled trial of multiple dosages of propranolol in children
with hemangiomas, funded by Pierre Fabre (registry number
V00400SB201).
Ethical Considerations
Data protection. The authors declare that they followed
their hospitals’ regulations regarding the publication of
patient information and that written informed consent for
voluntary participation was obtained for all patients. None
of the children photographed for this article were partici-
pants in the trial.
Right to privacy and informed consent. The authors
obtained informed consent for the mention of patients in
this article. All consent forms are in the possession of the
corresponding author.
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